In the context of a clinical trial strategy seeking to identify agents that could overcome or circumvent multidrug resistance, my laboratory identified the histone deacetylase inhibitor depsipeptide as an agent in preclinical development and a substrate for Pgp-mediated efflux. Because depsipeptide is avidly transported by Pgp, and because it induces MDR-1 in the constellation of genes altered by histone acetylation, we planned to eventually develop depsipeptide in combination with a Pgp modulator. However, in the Phase I setting, we made the serendipitous discovery that depsipeptide was highly effective in subsets of T cell lymphoma. While we have continued to be interested in our original strategy of preventing the emergence of resistance to this agent, we have pursued the use of depsipeptide as an orphan drug in T cell lymphoma, using both laboratory and clinical strategies.Our multi-institutional clinical trial for cutaneous and peripheral T cell lymphoma has enrolled 100 patients to date, divided into 6 cohorts. Cohort 1, patients with cutaneous T cell lymphoma with fewer than 2 systemic chemotherapy regimens, is complete and a manuscript is in preparation. The responses to depsipeptide are at times dramatic and have been very durable. As examples, one patient has received therapy continuously for over 5 years, remaining in a partial remission. Another patient remains in complete remission off of therapy for over 3 years. Gloucester Pharmaceuticals obtained Fast Track and Orphan Drug status from the FDA for development of this therapy for CTCL. A registration trial is nearing completion, and responses from our trial will be included in the NDA package. NCI CTEP and our Cancer Therapeutics Branch (now Medical Oncology Branch) largely pushed the development of this agent alone during a period in which Fujisawa Pharmaceuticals debated the relative merits of becoming involved in an oncology development platform. Responses with PTCL are also durable and Gloucester has developed a registration trial for that indication as well. The trial has a major second objective in addition to proving efficacy in the various histologies. That is confirmation of the safety of the agent. EKG abnormalities have been noted following treatment and a great deal of effort has gone into demonstrating the lack of myocardial damage associated with administration of this agent. One final concern is under evaluation -- in clinical trials sponsored by CTEP across the nation there were 5 unexpected deaths associated with depsipeptide among over 500 patients treated. While most of these patients had severe underlying cardiac disease, the potential contribution of depsipeptide treatment to these events is under study. Our ability to intensively characterize the cardiac effects of depsipeptide, an effective agent in a rare disease, is an excellent example of the critical role that the intramural program can play in drug development. Our first review of cardiac safety data appeared in Clinical Cancer Research in June 2006. The trial has a significant translational component that has consumed a major fraction of my laboratory resources. We have developed a quantitative immunoblot assay for detecting and quantitating histone acetylation in patient samples, principally peripheral mononuclear cells as a surrogate. Results from these assays are currently being compared to pharmacokinetic data. We have also evaluated gene expression - including CD25, p21, and MDR1 by RT-PCR, finding that only MDR1 expression is induced sufficiently following depsipeptide for routine assay in patient mononuclear cells. MDR1 is also analyzed in tumor samples before therapy is initiated and then at the time of disease progression. Additional studies include a Phase I trial of depsipeptide on a day 1, 3, and 5 schedule in hopes of achieving a more continuous drug effect.